Abstract
Porphyromonas gingivalis, a bacterium associated with periodontal disease, is a suspected cause of Alzheimer’s disease. This bacterium is reliant on gingipain proteases, which cleave host proteins after arginine and lysine residues. To characterize gingipain susceptibility, we performed enrichment analyses of arginine and lysine proportion proteome-wide. Genes differentially expressed in brain samples with detected P. gingivalis reads were also examined. Genes from these analyses were tested for functional enrichment and specific neuroanatomical expression patterns. Proteins in the SRP-dependent cotranslational protein targeting to membrane pathway were enriched for these residues and previously associated with periodontal and Alzheimer’s disease. These ribosomal genes are up-regulated in prefrontal cortex samples with detected P. gingivalis sequences. Other differentially expressed genes have been previously associated with dementia (ITM2B, MAPT, ZNF267, and DHX37). For an anatomical perspective, we characterized the expression of the P. gingivalis associated genes in the mouse and human brain. This analysis highlighted the hypothalamus, cholinergic neurons, and the basal forebrain. Our results suggest markers of neural P. gingivalis infection and link the cholinergic and gingipain hypotheses of Alzheimer’s disease.
Highlights
Porphyromonas gingivalis (P. gingivalis), a keystone species in the development of periodontal disease is believed to play a pathogenic role in several systemic inflammatory diseases [1]
Amino acid proportions were mean averaged across multiple transcripts that were annotated to the same gene symbol
Ranked 15th are genes annotated to the nucleosome, which includes many histones (60 genes, 20.9% average proportion, area under the receiver operating characteristic curve (AUC) = 0.926, pFDR < 10-29)
Summary
Porphyromonas gingivalis (P. gingivalis), a keystone species in the development of periodontal disease is believed to play a pathogenic role in several systemic inflammatory diseases [1] This Gram-negative anaerobe is unique in its ability to secrete gingipain proteases, which are its primary virulence factors and are required for its survival in vivo [2]. P. gingivalis is asaccharolytic and uses gingipains to degrade host peptides for nutrition and energy These gingipain peptidases are cysteine proteases that cleave bonds after arginine (RgpA and RgpB) and lysine (Kgp) [3, 4]. These two positively charged amino acid residues facilitate binding of negatively charged nucleic acids [5, 6]. This electrostatic relationship suggests gingipains may severely disrupt host cell protein-RNA and proteinDNA interactions
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